Patients with asthma have an eosinophilic inflammation of the bronchial mucosa and display two distinct physiologic responses of the airways: bronchial hyperreactivity to nonspecific stimuli (BHR) and acute allergen-induced airflow obstruction following inhalation of specific allergens. There are strong clinical and epidemiological correlations between asthma and IgE production. Multiple established functions of IgE may contribute to asthmatic pathophysiology and blockers of IgE and its receptors are currently being studied as potential therapeutic agents. A number of murine models of asthma, including those established in this laboratory, have been utilized to examine the pathogenesis of two of the important aspects of the asthmatic response: allergen-induced eosinophilic inflammation of the airway mucosa and BHR. Using IgE-deficient mice (IgE-/-) previously generated by gene-targeting, we have shown that both eosinophilic airways inflammation and BHR (increased sensitivity to non-specific stimuli) can arise by IgE-independent pathways. To date, however, the existing models have not permitted analysis of other crucial features of the disease, acute airflow obstruction provoked by allergen inhalation and IgE-mediated amplification of local cellular and humoral immune responses in the bronchial mucosa. Novel approaches for the study of these responses have now been established by the P.I. and will be used to examine several hypotheses regarding the role of IgE. We hypothesize that allergen-specific IgE is a critical trigger of acute airflow obstruction following allergen inhalation and will address this question by bronchoprovocation studies in allergen-sensitized wild-type and IgE-/- mice. We have shown that IgE enhances CD23 expression and propose that this upregulation enhances the ability of B cells bearing IgE via CD23 to present antigen to allergen specific T cells. This hypothesis will be studied by testing the ability of B cells from wild-type, IgE-/-and CD23-/- mice to present antigen to antigen-specific T cells. Furthermore, we propose that IgE facilitates antigen focusing in the inflamed bronchial mucosa, leading to enhanced cellular and humoral responses in settings of recurrent allergen exposure and providing a mechanism for the phenomenon of allergic spread. We will compare the immune responses of wild-type and IgE-/- mice following bronchial allergen exposure performed in the presence and absence of actively-induced or passively administered specific IgE.